Relevance of Clinical Relevance

We are concerned by an article published in the April 2016 issue of Anesthesiology by Han et al.¹  entitled “Propofol-induced Inhibition of Catecholamine Release Is Reversed by Maintaining Calcium Influx.” The authors addressed the molecular mechanisms underlying propofol-induced hypotension and describe a number of proposed molecular mechanisms thought to underlie this clinical effect. They focus their study on one such mechanism: the effect of propofol on catecholamine release from rat PC12 neuroendocrine cells and isolated cortical nerve terminals. In contrast to a number of previous studies showing that propofol inhibits catecholamine release,^2,3  the authors report that when intracellular calcium concentration was maintained constant, catecholamine release was enhanced by propofol. Our principal concern is that enhanced catechoamine release was observed only at propofol concentrations greater than 10 μM, a value that the authors suggest represents a “clinically relevant concentration.”

The total plasma concentration of propofol required to produce loss of consciousness in 50% of subjects is 4.4 μg/ml (25 μM), while the concentration for preventing response to intubation in 50% of subjects is 17 μg/ml (98 μM).⁴  Importantly, studies of the total compared to free propofol concentrations in human blood show that more than 97% of total propofol is bound to blood constituents, largely to plasma proteins, and thus is pharmacologically sequestered.^5,6  While in principle a continuous propofol infusion at a standard rate of 100 μg kg⁻¹ min⁻¹ could produce a total blood propofol concentration of approximately 10 μM, the combined effects of metabolism, redistribution, and binding to plasma proteins and erythrocytes significantly reduce free blood propofol concentrations in vivo. The clinically relevant free propofol concentration is in the submicromolar range, with the most commonly cited value of 0.4 μM based on a widely cited and influential review by Franks and Lieb.⁷  They and others⁸  have called attention to the critical importance of using free anesthetic concentrations, which more accurately reflect effect-site concentration, in designing and interpreting experiments performed in vitro.

It is unlikely that a free blood propofol concentration of 10 to 100 μM will ever be encountered in clinical practice, an important detail when weighing the clinical applicability and relevance of an ex vivo study. The pharmacology of propofol, and other common anesthetic agents, has been extensively studied. To claim that the effects reported in the current study occur at a “clinically relevant concentration” misrepresents this body of research and can easily lead to erroneous conclusions. We hope that this letter can serve as a reminder of the fundamental importance of knowing where the field has been to avoid the pitfalls of the past.

Dr. Hemmings serves as an editor of Anesthesiology and the British Journal of Anaesthesia, he has received research funding from the National Institutes of Health (Bethesda, Maryland) and TEM International (München, Germany), and he has served as a consultant for Elsevier (Amsterdam, The Netherlands). Dr. Goldstein receives funding from the U.S. Department of Defense (Washington, DC) and Mallinckrodt Pharmaceuticals (Dublin, Ireland). Dr. Riegelhaupt declares no competing interests.